Elsevier

European Journal of Cancer

Volume 44, Issue 17, November 2008, Pages 2546-2554
European Journal of Cancer

Current Perspective
Hyperthermia adds to chemotherapy☆

https://doi.org/10.1016/j.ejca.2008.07.038Get rights and content

Abstract

The hallmarks of hyperthermia and its pleotropic effects are in favour of its combined use with chemotherapy. Preclinical research reveals that for heat killing and synergistic effects the thermal dose is most critical. Thermal enhancement of drug cytotoxicity is accompanied by cellular death and necrosis without increasing its oncogenic potential. The induction of genetically defined stress responses can deliver danger signals to activate the host’s immune system. The positive results of randomised trials have definitely established hyperthermia in combination with chemotherapy as a novel clinical modality for the treatment of cancer. Hyperthermia targets the action of chemotherapy within the heated tumour region without affecting systemic toxicity. In specific clinical settings regional hyperthermia (RHT) or hyperthermic perfusion has proved its value and deserve a greater focus and investigation in other malignancies. In Europe, more specialised centres should be created and maintained as network of excellence for hyperthermia in the field of oncology.

Section snippets

Hyperthermia or heat shock exposure: Arrhenius relationships from the molecule and cell to the clinic

Hyperthermia can be defined as controlled temperature elevation by targeting the heating field to the malignant tumour as well as the surrounding tissue, organ, part of body or even to the whole body. Following the results of profound research starting in the early 1970s for exponentially growing cells when exposed to heat shock above a threshold temperature – in general – a strict temperature–time relationship was noted. This is specific for the individual cell line, and different in the

Enhancement of drug cytotoxicity by hyperthermia: its reality at clinically relevant temperatures

Heat modifies the cytotoxicity of many chemotherapeutic agents (see Table 1).8, 9, 10, 11, 12, 13 The extent of ‘thermal chemosensitisation’ both in vitro and in vivo can be quantified by the quotient of the clonogenic cell growth or tumour cell growth or tumours treated either with the drug alone or with the same drug at elevated temperature. The thermal enhancement ratios (TER) for certain antineoplastic agents at two different temperatures (41.5 °C versus 43.5 °C, respectively) are given in

Cell lethality and oncogenic potential: what do we pay for the enhancement?

Heat could theoretically enhance both the cytotoxic and oncogenic potential of the drugs. Examination of transformation incidences expressed as a function of surviving fraction showed that for a given level of cell killing the combination of heat and, e.g. cisplatinum resulted in fewer transformants per surviving cell than for cisplatinum alone.19 Chemotherapy behaves in a manner similar to X-rays combined with heat, i.e. heat appears to convert sublethal damage to lethal damage, thus reducing

Hyperthermia as targeted therapy: perspective for delivery of anticancer agents

For those drugs which show temperature-dependent enhancement, the rationale for their combined application is that hyperthermia ‘targets’ the action of the chemotherapeutic agent within the tumour region with elevated temperatures without affecting systemic toxicity. There are new biological aspects that have to be transferred into clinical research.26 Hyperthermia can be used to enhance the delivery of drugs to the volume targeted by heat. However, microvascular damage that is caused by

Hyperthermia combined chemotherapy-induced necrosis: the role of released HSP and the immune response

The antineoplastic properties of chemotherapeutic agents are mainly based upon their ability to induce either a necrotic or apoptotic programmed cell death. Whereas necrosis is marked by a passive pathological cell damage followed by an inflammatory response, apoptosis represents a genetically controlled, active death programme.36, 37 Heat treatment induces both, apoptosis and necrosis, and the form of death changes from apoptosis to necrosis above a certain threshold temperature.38, 39 The

Combination trials: clinical application and results

The current interest in hyperthermia came into the limelight again in the beginning of 2000, where the medical community started re-addressing both the biological and clinical usefulness of this modality.58, 59, 60, 61 For many years, it has been an unproven dogma in hyperthermia research that antineoplastic heat action requires temperatures >43 °C in the clinic. The thermal isoeffect dose (TID) concept based upon pre-clinical in vitro results was – in simple analogy – transferred into the

Clinical aspects for future directions

In the past decade, combined use of local hyperthermia and radiation compared to radiation alone has clearly been shown to have clinical potential for relatively ‘superficial’ malignant tumours92, 93 in the appropriate situation, especially in recurrent breast cancer,94 both in terms of response rate and local control. At present, we are witnessing the coming of age for regional ‘deep’ hyperthermia (RHT, PBH and HIPEC) as a new treatment component for malignancies in general and if combined

Conflict of interest statement

None declared.

Acknowledgements

Thanks to Lars Lindner, Katharina Tschoep, Valeria Milani and Elfriede Noessner for their suggestions and critical and insightful comments on the manuscript and to Martina Lahm for her writing assistance.

References (103)

  • M. Franckena et al.

    Long-term improvement in treatment outcome after radiotherapy and hyperthermia in locoregionally advanced cervix cancer: an update of the Dutch deep hyperthermia trial

    Int J Radiat Oncol Biol Phys

    (2008)
  • D.L. Carter et al.

    Magnetic resonance thermometry during hyperthermia for human high-grade sarcoma

    Int J Radiat Oncol Biol Phys

    (1998)
  • J. Overgaard et al.

    Randomised trial of hyperthermia as adjuvant to radiotherapy for recurrent or metastatic malignant melanoma. European Society for Hyperthermic Oncology

    Lancet

    (1995)
  • R. Valdagni et al.

    Report of long-term follow-up in a randomized trial comparing radiation therapy and radiation therapy plus hyperthermia to metastatic lymphnodes in stage IV head and neck patients

    Int J Radiat Oncol Biol Phys

    (1994)
  • E. Gortzak et al.

    A randomised phase II study on neo-adjuvant chemotherapy for “high-risk” adult soft-tissue sarcoma

    Eur J Cancer

    (2001)
  • O. Glehen et al.

    Peritoneal carcinomatosis from digestive tract cancer: new management by cyroreductive surgery and intraperitoneal chemohyperthermia

    Lancet Oncol

    (2004)
  • E. de Bree et al.

    Intraperitoneal chemotherapy with taxanes for ovarian cancer with peritoneal dissemination

    Eur J Surg Oncol

    (2006)
  • A. Sapareto et al.

    Hyperthermic effects on survival and progression of CHO cells

    Cancer Res

    (1978)
  • K.D. Bauer et al.

    Arrhenius analysis of heat survival curves from normal and thermotolerant CHO cells

    Radiat Res

    (1979)
  • W.C. Dewey

    Arrhenius relationships from the molecule and cell to clinic

    Int J Hyperthermia

    (1994)
  • P. Vaupel et al.

    Blood flow, oxygen and nutrient supply, and metabolic micro-environment of human tumors: a review

    Cancer Res

    (1989)
  • D.E. Thrall et al.

    Thermal dose is related to duration of local control in canine sarcomas treated with thermoaradiotherapy

    Clin Cancer Res

    (2005)
  • E.L. Jones et al.

    Randomized trial of hyperthermia and radiation for superficial tumors

    J Clin Oncol

    (2005)
  • G.M. Hahn

    Potential for therapy of drugs and hyperthermia

    Cancer Res

    (1979)
  • J.B. Marmor

    Interactions of hyperthermia and chemotherapy in animals

    Cancer Res

    (1979)
  • R. Engelhardt

    Hyperthermia and drugs

    Recent Res Cancer Res

    (1987)
  • O. Dahl

    Interaction of hyperthermia and chemotherapy

    Recent Res Cancer Res

    (1988)
  • J.M.C. Bull

    An update on the anticancer effects of a combination of chemotherapy and hyperthermia

    Cancer Res

    (1984)
  • M. Urano et al.

    For the clinical application of thermochemotherapy given at mild temperatures

    Int J Hyperthermia

    (1999)
  • D.F. Deen et al.

    Isobologram analysis of X-ray–BCNU interactions in vivo

    Radiat Res

    (1979)
  • F. Valeriote et al.

    Synergistic interaction of anticancer agents: a cellular perspective

    Cancer Chemother Rep

    (1975)
  • J. Haveman et al.

    Effect of hyperthermia on the cytotoxicity of 2′,2′-difluorodeoxycytidine (gemcitabine) in cultured SW1573 cells

    Int J Cancer

    (1995)
  • C. van Bree et al.

    Effectiveness of 2′,2′-difluorodeoxycytidine (gemcitabine) combined with hyperthermia in rat R-1 rhabdomyosarcoma in vitro and in vivo

    Int J Hyperthermia

    (1999)
  • R.C. Miller et al.

    Interaction of hyperthermia and chemotherapy agents; cell lethality and oncogenic potential

    Int J Hyperthermia

    (1994)
  • R.C. Miller et al.

    Interaction of heat with X-rays and cis-platinum; cell lethality and oncogenic transformation

    Int J Hyperthermia

    (1989)
  • J.W. Grisham et al.

    Cycle-related toxicity and transformation in 10T1/2 cells treated with N-methyl-N′-nitro-N-nitrosoguanidine

    PNAS

    (1980)
  • P.J. McCormick et al.

    Differential cell cycle phase specifity for neoplastic transformation and mutation to ouabain resistance induced by N-methyl-N′-nitro-N-nitroguanidine in synchronized C3H 10T1/2 cells

    PNAS

    (1982)
  • H.H. Kampinga et al.

    Hyperthermic radiosensitization: mode of action and clinical relevance

    Int J Radiat Biol

    (2001)
  • C.R. Hurt et al.

    Genomic instability and enhanced radiosensitivity in Hsp70.1- and Hsp70.3-deficient mice

    Mol Cell Biol

    (2004)
  • C.R. Hunt et al.

    Hyperthermia activates a subset of Ataxia-Telangiectasia mutated effectors independent of DNA strand breaks and heat shock protein 70 status

    Cancer Res

    (2007)
  • M.W. Dewhirst

    Future directions in hyperthermia biology

    Int J Hyperthermia

    (1994)
  • R.K. Jain

    Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy

    Science

    (2005)
  • C.W. Song et al.

    Implications of increased tumor blood flow and oxygenation caused by mild temperature hyperthermia in tumor treatment

    Int J Hyperthermia

    (2005)
  • J. Gellermann et al.

    Non-invasive MR-thermography of soft tissue sarcomas during regional hyperthermia: correlation with response and direct thermometry

    Cancer

    (2006)
  • M.B. Yatvin et al.

    Design of liposomes for enhanced local release of drugs of hyperthermia

    Science

    (1978)
  • D. Needham et al.

    A new temperature-sensitive liposome for use with mild hyperthermia: characterization and testing in a human tumor xenograft model

    Cancer Res

    (2000)
  • L.H. Lindner et al.

    Novel temperature sensitive liposomes with prolonged circulating time

    Clin Cancer Res

    (2004)
  • Jones E, Vujaskovic Z, Dewhirst M, et al. An update of the duke experience for thermally sensitive liposomes containing...
  • A. Zintchenko et al.

    Temperature dependent gene expression induced by PNIPAM-based copolymers: potential of hyperthermia in gene transfer

    Bioconjug Chem

    (2006)
  • E. Wagner

    Programmed drug delivery: nanosystems for tumor targeting

    Expert Opin Biol Ther

    (2007)

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    ☆

    Source of support: Helmholtz Gemeinschaft Deutscher Forschungszentren – VH-VI-140 Clinical Hyperthermia and Related Technology SFB455 – Virale Funktionen und Immunmodulation Deutsche Krebshilfe e.V.

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